Together with joining sex steroids, this new SHBG homodimer itself serves as a beneficial ligand having a particular, higher attraction receptor (Roentgen

Into the human beings, each SHBG monomer subunit include a beneficial 373 amino acid polypeptide having three oligosaccharide front chains as well as 2 disulfide securities (2). Each SHBG subunit include an effective steroid joining website ready joining DHT, testosterone, or estradiol, such that new mature SHBG homodimer possess a few distinct steroid binding websites (29). Moreover, for each and every monomer include one or two ?-sheets which can be essential in the new dimerization of your mature SHBG glycoprotein. Particularly, 7 hydrogen bonds is shaped along side user interface of one’s ?-sheets such that a few carried on 14-stuck ?-sheets are formed about mature homodimer (29;30).

Just like other steroid hormonal-binding glycoproteins such as for instance cortisol-joining globulin otherwise thyroxine-binding globulin, adult SHBG include oligosaccharide side stores, therefore the structural team of the carbs moieties are certain so you’re able to per joining glycoprotein (31). Specifically, for each subunit of SHBG homodimer is actually described as three oligosaccharide moieties, an enthusiastic O-linked glycosylation site in the Thr7, and Letter-connected sites during the Asn 351 and you can Asn 367 (32–34). Whilst oligosaccharide top-stores to your SHBG do not appear to be critical for the newest glycoprotein’s steroid-joining passion (34), just like the biologic function present in almost every other glycoproteins, SHBG glycosylation is generally essential in the fresh new glycoprotein’s telecommunications having particular cell-body receptors (35).

_SHBG) present on the plasma deze website membranes of target cells (8;10;11;36;37). Only steroid-free SHBG appears to bind to R_SHBG; however, once SHBG is bound to the receptor, sex steroids can then activate the anchored SHBG-R_SHBG complex (8). Moreover, adding additional complexity to the system, not all steroids that bind to the SHBG-R_SHBG complex function as agonists; some are antagonists (8). Moreover, some steroids such as DHT may function as either an agonist or antagonist for the system, depending on the specific target cell type (8;38). Although the full downstream effects of SHBG-R_SHBG complex activation remain unclear, complex activation appears to affect target cell growth in addition to modulating the transcriptional activity of classic intracellular steroid hormone receptors (8).

SHBG may also actively participate in the uptake of sex steroids by target tissues through interactions with megalin, an endocytic receptor distinct from R_SHBG (9). Although the uptake of SHBG-bound sex hormones via the megalin-mediated pathway is controversial (39), such findings support an expanded role of SHBG in sex steroids physiology.

SHBG Gene Build and Splice Alternatives

The SHBG gene, located on the chromosome 17p12>p13, consists of eight exons separated by seven small introns (2;40;41). Exon 1 encodes for the nacent protein’s 29 amino acid secretion signal polypeptide (2), while the remaining exons [2–8] encode two contiguous laminin G–like (LG) domains (41). The amino-terminal LG domain encoded by exons 2–4 contains the steroid-binding site, the dimer interface, and several cation-binding sites (42). A ten amino acid sequence (residues 48–57) within exon 3 appears to correspond to the R_SHBG-binding domain (43).

Although hepatocytes are the primary source of plasma SHBG (44), extrahepatic tissues, including testis, prostate, ovary, endometrium, breast, placenta and hypothalamus also express SHBG mRNA in humans (45–51). In fact, recent evidence suggests that the transcriptional control of SHBG gene expression is extremely complex and is regulated by at least three distinct promoters (P_L, P_T, and P_N) which are expressed differentially in various human tissues (52).

Activation of the downstream promoter (P_L), results in the production of the most common SHBG mRNA transcript [exon1L-8] (52). The exon IL-8 transcript is predominantly expressed in hepatocytes and encodes for all eight exons present in the SHBG gene. P_L activation in the testis results in an identical eight-exon mRNA; however, distinct post-translational processing of the testicular transcript results in the production of androgen binding protein (ABP) instead of mature SHBG (45;53). In addition to the liver and testis, the 1L-8 mRNA transcript is also expressed in the human prostate, breast and regions of the brain (52). In the testis, activation of a second SHBG promoter (P_T), located 1.9 kb upstream of P_L, produces a second major mRNA transcript (45;52). In addition to possessing an unique 5? end amino acid sequence (exon 1T), the second testicular transcript also lacks exon 7(45;52). Recently, Nakhla and colleagues described a third SHBG gene promoter (P_N), located within intron 1 of the adjacent FXR2 gene (52). Similar to P_L and P_T transcripts, P_N transcripts possess a distinct first exon (1N). Differential activation of the three promoters triggers alternative splicing of SHBG exons which, in turn, may result in the expression of at least 19 unique SHBG transcripts (52). Furthermore, the pattern of SHBG transcript expression differs in normal tissues with P_L-, P_T-, and P_N– derived transcripts being most abundantly expressed in the liver, testis, and prostate, respectively (52). Interestingly, alternative splicing of SHBG is more pronounced in certain cancer cell lines compared with normal tissues (52) ( Figure 1 ). Although Nakhla and colleagues hypothesize that only certain P_L-derived transcripts produce stable SHBG isoforms, the potential biologic significance of alternatively spliced SHBG gene transcripts remains unclear (52).